Finding ways to preserve or replace brain neurons that are vulnerable to disease or injury remains an important therapeutic goal. The mammalian olfactory bulb is the only brain structure identified to date that is known to regularly replace neurons in adulthood. Proliferating neural stem cells in the forebrain subventricular zone (SVZ) give rise to thousands of neuroblasts daily that migrate in the rostral migratory stream to the olfactory bulb and differentiate as inhibitory interneurons. The vast majority of new neurons develop as granule cells, and these modulate the activity of excitatory output neurons, the mitral cells, through synapses that form on their dendritic processes. Pre-existing granule cells gradually die, and their replacement by adult-born granule cells maintains the overall integrity of olfactory bulb circuitry, and the functional capabilities of this sensory system. About half of new granule cells die over the first few weeks of their development in the bulb, with only a fraction o the population surviving long- term. How this cell turnover is controlled within the bulb, what determines which neurons, and how many, will live or die, and how new neurons form synapses within pre-established circuits is not well understood. Much more is known is about how these processes are controlled during early development, and there may be similarities in the mechanisms involved. Trophic factor signaling is one such mechanism that operates to sculpt the sizes of neuronal populations and their connections during brain development, and continues to maintain neuron morphology and synaptic plasticity in adults. Using transgenic mice, the work described in this proposal will first determine if increasing endogenous trophic factor signaling in the bulb promotes greater survival of new granule cells under normal conditions. Secondly, granule cell survival is reduced by suppressing neural activity and by pathology associated with Huntington's disease, and trophic factor over-expression will be tested for its ability to rescue new neurons under these adverse conditions. Finally, the morphological development of new cells will be monitored to determine whether increased trophic signaling can foster their functional integration by enhancing dendrite growth and synapse formation. Identifying factors in the adult CNS that promote the survival and development of SVZ-derived progenitors under normal, as well as pathological conditions, will have important implications for adapting adult neural stem cells for therapeutic purposes. PUBLIC HEALTH RELEVANCE: In adult brain, only the olfactory system has the capacity to regularly replace older neurons with new neurons generated from SVZ stem cells. Understanding the mechanisms that control this process and favor the survival and integration of new neurons has practical implications for the design of cell-based therapeutic strategies aimed at treating neurological disorders. PUBLIC HEALTH RELEVANCE: The olfactory forebrain contains the only population of neurons that are regularly replaced by new neurons born in the adult brain. The mutation that causes Huntington's disease (HD), and conditions that reduce neural activity, inhibit the survival of new neurons in this system. This research project will test if neurotrophic factor signaling regulates the normal neuron replacement process, and if increasing trophic factor availability rescues adult-born neurons from death caused by HD pathology or suppressed network activity.